Opioids and Respiratory Depression

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The main cause of death due to opioid overdose is respiratory depression. In other words, the brain of a person under the influence of opioids can simply forget to breathe. In today’s episode, we talk with Dr. Erica Levitt, associate professor in the Departments of Pharmacology and Anesthesiology at University of Michigan Medical School, who is trying to explain this connection, with the hope of maintaining the powerful pain relieving effects of opioids without their potentially deadly effects.

More Resources:

Dr. Erica Levitt Profile

Transcript:

Kelly Malcom:

Welcome to the Fundamentals, a podcast where we explore biomedical research here at Michigan Medicine. Research is fundamental to University of Michigan's mission to improve the world. On each episode, we'll meet the people behind the research, learn more about their fields and the fundamental questions they are trying to answer. I'm Kelly Malcolm, a science writer and communication strategist for the University of Michigan Medical School. This season, we'll start by explaining a little bit of the history behind the questions our experts are asking, and get a glimpse into the future of healthcare. Between 5,000 and 8,000 years ago, people in the Mesopotamian region discovered that a milky fluid from the seed pods of a certain poppy flower could produce intense feelings of euphoria and alleviate pain. The substance, dubbed opium, was much later refined into morphine in the early 1800s, by German pharmacist Friedrich Sertürner thus, creating one of the first medicinal, and psychoactive drugs derived from a natural product.

The pursuit of opioids has had deadly consequences over millennia. By the 1830s, one third of all lethal poisoning was due to opium. Scientists have worked to make opium safer while maintaining its ability to relieve pain in the process developing codeine, heroin, fentanyl, and many other related drugs. Almost 200 years after the creation of morphine, a newer class of opioid, oxycodone would kick off the first wave of an opioid epidemic in the US that persists to this day. The main cause of death due to overdose is respiratory depression. In other words, the brain of a person under the influence of opioids can simply forget to breathe. This fact makes using opioids as pain relievers risky, even in a clinical setting. Despite this well-known effect, scientists don't fully understand how opioids depress breathing. Researchers, like today's guest, Dr. Erica Levitt, associate professor in the Departments of Pharmacology and Anesthesiology at U of M, are trying to figure out why. Unraveling this mystery could help clinicians maintain the powerful pain relieving effects of opioids without its potentially deadly effects. Welcome to the show, Dr. Levitt.

Dr. Erica Levitt:

Thanks for having me. I'm happy to be here.

Kelly Malcom:

Hey, we're going to open with the first question that I think a lot of people don't really understand is how do opioids work in the brain?

Dr. Erica Levitt:

Yeah, so opioids like fentanyl act on mu opioid receptors that are expressed on neurons in the brain, and generally activation of these receptors inhibits the activity of the neurons. So that's what happens brain-wide. In the breathing centers opioids inhibit those neurons as well. A lot of people don't necessarily think of breathing as a motor behavior, but it really is. So it requires coordinated activity of different groups of muscles, and that coordinated activity is generated by central pattern generators in the brain. And those central pattern generators are a collection of neurons in the brain, and some of them happen to have opioid receptors that inhibit them.

Kelly Malcom:

And the inhibition is what? Dulls pain?

Dr. Erica Levitt:

Yes. So it dulls pain, it depresses breathing, and also causes the euphoric, or the high that is associated with opioid use.

Kelly Malcom:

Can you tell us a little bit, why is there a receptor that causes euphoria to begin with? Why would that exist?

Dr. Erica Levitt:

The ultimate question why, or I thought you were going to ask why do opioid... Why do we have this endogenous receptor that can make us stop breathing?

Kelly Malcom:

Exactly, yes.

Dr. Erica Levitt:

I get that question a lot too. So from the breathing standpoint, so we have these receptors in our bodies. We also make endogenous opioid peptides to bind to these receptors. And so, we have the receptors because of the endogenous peptides, not because we're using poppies. And you're never going to overdose on the level of endogenous opioid that exists. So it's not a risk, evolutionarily at least for us to have these receptors on breathing control centers. So my theory is that it's... Or how I always answer this question is that having this way to endogenously decrease breathing is compensation for situations where you might have heightened breathing and maybe hyperventilation. So things like stress, or pain, those will elevate breathing, and they also release endogenous opioids which then will decrease the breathing back into a good range, a normal range so you're not hyperventilating or having very off blood gases. So that's my theory is that, it's compensation. And then from the euphoria side, we as species need motivation, motivation to eat, motivation to breed, motivation to keep our species alive frankly, and keep going. So it's all involved in that motivation circuitry.

Kelly Malcom:

So opioids have been around for a very long time. Why isn't there more known about what they're doing in the brain? I mean, you just explained that, but why don't we know why it's slowing breathing and all of those other effects?

Dr. Erica Levitt:

So we knew a lot more about how opioids work in the pain and the euphoria-generating centers because they've been studied a lot longer. But people haven't studied opioids effects in the breathing control network for as much, I guess for a couple of reasons. So one, for a while, the breathing suppression was considered a side effect of opioids, and with opioids with high therapeutic index, it was a manageable side effect. So it wasn't until the introduction of fentanyl or the other ultra potent opioids into the illicit drug supply that we see the escalating overdoses due to respiratory depression that more people are now studying why respiratory depression happens, in order to try to maybe circumvent the respiratory depression.

Kelly Malcom:

Okay. So the opioids that are used in your healthcare settings don't have that strong breathing depression effect.

Dr. Erica Levitt:

So there's a range. So the prototypical opioid agonist, that's been around forever a long time is morphine, right? It's derived from directly from the opium poppy, and it's more of a partial agonist. So it has a much slower onset, less risk of severe respiratory depression, or it's at least titratable, and it's understandable. Fentanyl is also clinically used. It's used in procedures in the hospital for a long time, but it's recent addition into the illicit drug supply sometimes unknowingly is what has really increased that overdose risk.

Kelly Malcom:

Is there something special about fentanyl in comparison to other opioids that makes it especially dangerous?

Dr. Erica Levitt:

Yeah, there's some theories about that. So fentanyl is, at least in vivo, or so in people, or in animals, is more potent, we'll say tenfold more potent than morphine. So that means you don't need as much drug to activate the receptor. And then it also is really lipophilic, which means it likes to live in lipids and our cell membranes are all made of lipids. And it can get into our brains really quickly. And also it maybe have some interesting interactions with our membranes where it can hang around at a higher concentration nearby the receptors. That's one theory.

So I think that the... And the pharmacokinetics of fentanyl are also fairly rapid. So having quick access of a higher potency drug suppresses breathing quickly. And that maybe more quickly, so the compensatory mechanisms can't kick in. So if as you slow your breathing, your oxygen levels drop and your CO₂ levels rise, both of those things will stimulate compensatory mechanisms, especially the rising CO₂ to drive breathing. So if you're suppressing breathing quicker, then you can't respond to that rise in CO₂ that also might contribute to the higher lethality.

Kelly Malcom:

So why did you decide to study breathing, versus maybe studying addiction, like a lot of people have done?

Dr. Erica Levitt:

Yeah, so this has been an evolution in my career. I started out studying opioid receptor pharmacology, and opioid tolerance that develops with repeated use of opioids. And in the process of trying to understand opioid tolerance, I realized that tolerance to the respiratory depressant effects of opioids lags behind the pain relieving or the euphoric effects, and we wanted to know why. So I started looking at opioid receptors on neurons that control breathing. And then the more I read realized we really didn't understand how opioids caused respiratory depression, and really that well at all, especially compared to what was known in the pain and the reward pathways. So that's what I decided I wanted to study. It was also the 2016 start of the opioid epidemic, and I thought it was an important area to study. So when I started my lab in 2016, that's what we focused on was trying to understand how opioids affect the neurons in the brain stem that control breathing. And we've been doing it ever since.

Kelly Malcom:

Okay. So let's try to explain what exactly is happening. What do we know about what's happening when your breathing is depressed by an opioid?

Dr. Erica Levitt:

There are multiple groups of neurons that control breathing. So one of them sets the rhythm of breathing. So there's opioids expressed in those neurons that set the rhythm. There are other neurons in the pons that control the rate, so they can modulate those rhythm generating neurons to control the speed at which we breathe. So there's strong expression of opioid receptors on those neurons. So by decreasing, that's an excitatory input to the rhythm generating neurons. So by decreasing that excitatory input, you're also reducing the drive to breathe, which is a problem. And then those neurons in the pons also control our upper airways. So another effect that opioids have other than just suppressing breathing is that they cause obstructive apneas, so they cause upper airway impairments as well. And those neurons in the pons also controlled upper airways. So multiple things that opioids can be doing.

Kelly Malcom:

Okay. So can anything reverse the effects of opioid unbreathing?

Dr. Erica Levitt:

The standard of care for opioid overdose is naloxone or Narcan. So that's internasal naloxone, and it will very rapidly reverse an opioid overdose in most cases, which is really good, life-saving. It does have some drawbacks in that it requires a bystander to be there and to be able to administer it. Also, since it's an antagonist of the opioid receptor, it will reverse all opioid effects simultaneously leading to withdrawal which is very unpleasant and also uncontrolled pain if someone was taking an opioid for pain relief. So those are some drawbacks that would be nice to be able to circumvent or get around with something that would stimulate, or support breathing that doesn't necessarily just block the opioid receptor.

Kelly Malcom:

Right, because then you're not getting the good effects either.

Dr. Erica Levitt:

Right, exactly.

Kelly Malcom:

Okay. Studies are showing that serotonin can counter respiratory depression in rodents. Do we know why? And maybe we should open with what serotonin is.

Dr. Erica Levitt:

Yeah, serotonin is a neuromodulator. It's often thought of in mood. So SSRIs are very commonly used drugs. They elevate serotonin or they block the reuptake of serotonin. But serotonin has a lot of other effects in the body and in the brain, and one of them is it actually helps to stimulate breathing. The receptors. So there's 14 different serotonin receptors, and so agonists for all... Or not all maybe but many of those receptors have been shown to stimulate breathing alone, and also stimulate breathing in the presence of opioids. So actually, it's good, It's promising, but it makes things a little bit more confusing because since these receptors have opposing intracellular mechanisms, so it doesn't help us understand how these receptors are working, because there's so many that you would think could be working in opposition, but really they're having all the same effect.

So what we're doing is we're taking a step back to try to look at the serotonin circuitry, to understand how the endogenous serotonin neurons. So serotonin is produced by neurons in the brain. So we're trying to understand what those neurons are doing initially on their own in the brain to control breathing, and in the presence of opioids to then maybe try and understand how these different agonists are working.

Kelly Malcom:

Got it. So does that mean you could take antidepressant for breathing, or would it have to be in a different form?

Dr. Erica Levitt:

I think it would need to be a different... I think they are too slow acting in order to really have an effect on breathing. So that's why direct agonists might be a better approach.

Kelly Malcom:

For our listeners, can you define what an antagonist and agonist is?

Dr. Erica Levitt:

An agonist is a chemical that binds to a receptor and activates it, and an antagonist is a chemical that binds through a receptor and blocks the binding of other agonists. So it prevents the ability of the receptor to be activated.

Kelly Malcom:

Okay. So can you talk to us a little bit about the potential of psychedelics as maybe treatments, or therapies for overdose. I know you mentioned that, but how would that work?

Dr. Erica Levitt:

So psychedelics, the classic ones target 5-HT2A receptors, and serotonin 2A receptors. So these are one subtype of serotonin receptor, and these receptors have been shown to stimulate breathing, which is good. There are another subtype that's very closely related, the serotonin 2C subtype of serotonin receptor that also stimulates breathing. But has maybe some less risk of the hallucinogenic effects that are associated with psychedelics. So it could be that targeting the 2C receptor would be a good approach to combat respiratory depression without the psychedelics like hallucinogenic effects. But regarding the psychedelics, they are being tried for treatment of a whole host of mental health conditions, including opioid use disorder. So I think it's also important, and we're looking into what happens to opioid-induced respiratory depression in at least rodents that are treated with psychedelics, or the serotonin 2A receptor agonists.

Kelly Malcom:

Okay, but we're not telling people to take it.

Dr. Erica Levitt:

No, we're not telling people to take psychedelics. Psychedelics alone, it seems are not going to stimulate breathing enough to prevent an overdose. So that's why we're trying to look now more at the serotonin 2C receptor, and see if that could maybe just support breathing in a way that would make opioids just a little bit less risky. A little bit less than the effect on breathing, but we have a long way to go.

Kelly Malcom:

I guess that was going to be my next question is what is the goal? Is it to make fentanyl less dangerous, to come up with an alternative to fentanyl that doesn't affect breathing, or to make a better Narcan?

Dr. Erica Levitt:

All of those are potential options. Our focus right now is to find... Looking at not necessarily a better Narcan, but a way to stimulate breathing, an alternate to stimulate breathing that doesn't rely on the opioid receptor. There are others who have worked on making a better version of Narcan. Longer acting antagonist because one of the other drawbacks of Narcan is that it will wear off often sooner than the agonist will wear off. So there are now longer acting versions of antagonist available. So that's another approach that others have used.

Kelly Malcom:

Okay. So let's walk through a hypothetical. We can do a clinical situation and maybe somewhere out in the community. So in a clinical setting, if we have a better understanding of the breathing effects, what would be the ideal maybe improvement of the treatment for pain?

Dr. Erica Levitt:

So in a clinical setting, you can very closely monitor people, and we do a good job of that. And there's a lot of supportive care already available, and fentanyl already is short-acting and used clinically, and that's really good. I know there are also definitely groups looking at pain relief options that don't use the opioid receptor at all, which would be a nice alternative for some people, especially some types of pain opioids don't work as well so it would be nice to have a non-opioid pain reliever.

Kelly Malcom:

And so in the community, people maybe suffering from opioid use disorder or with opioid use disorder what would be the best outcome?

Dr. Erica Levitt:

Yeah, so this is a question I think about a lot because we're far right. We do our work in rodents, so we're far from directly being in the community. But the real goal is to eventually treat the opioid use disorder. But in order for people to enter and complete opioid use disorder treatment, they need to get there. And so by first stabilizing breathing and preventing people from dying, I think it's an important first step. And I think it actually perhaps achievable. Treating the opioid use disorder is a big task. Stabilizing breathing is something that I think we can do.

Kelly Malcom:

So what is next for your particular lab?

Dr. Erica Levitt:

Yes. So there are a lot of disorders that breathing is an issue. So one of another branch of the lab is looking at sudden unexpected death and epilepsy. So in a certain population of epileptic patients, they'll have a seizure which somehow shuts down the brainstem control of breathing centers, and people stop breathing. They can do this without even being aware. A lot of times it happens in sleep. And the scary thing is that right now there's no indication of when someone might stop breathing, what is the seizure that will cause them to stop breathing? And so we're trying to look at if there are changes in the breathing network that might be indicators, or even just what happens in models of this disorder to cause breathing suppression. So slightly different topic breathing related.

Kelly Malcom:

Got it. Okay. So once you have better understanding of how breathing is controlled, you can look at conditions where the control of breathing is involved and potentially intervene.

Dr. Erica Levitt:

That's the goal.

Kelly Malcom:

So who are your major collaborators and did you want to give a shout-out to anyone?

Dr. Erica Levitt:

Sure. I'll shout out to my great collaborators in the Department of Pharmacology at the University of Michigan, working on opioids specifically. We have John Traynor, Will Birdsong, Carrie Ferrario. And then from the breathing perspective, we have Peng Li, Paul Jenkins, and Lori Isom, who's a very supportive chair and I appreciate very much. Also, friends in the Opioid Research Institute have really given me some clinical pearls to apply, and think about when I'm doing my research.

Kelly Malcom:

Well, it's been wonderful having you on the Fundamentals, Dr. Levitt. It's been incredibly educational. I learned a lot about opioids, so thank you again.

Dr. Erica Levitt:

You're welcome. Thank you for having me. It's been fun.

Kelly Malcom:

The Fundamentals is produced by the Michigan Medicine Department of Communication in partnership with the University of Michigan Medical School. Find us and subscribe wherever you listen to podcasts.